The intermediate state of HTLV-1 infection, often found in individuals dually infected with Strongyloides stercoralis (S. stercoralis) and HTLV-1, is assumed to be a preleukemic state of adult T-cell leukemia (ATL). To investigate the e ects of S. stercoralis superinfection on the natural history of HTLV-1 infection, we characterized peripheral blood samples of these individuals in Okinawa, Japan, an endemic area for both HTLV-1 and S. stercoralis and we studied e ects of the parasite antigen on T-cells. The dually infected individuals showed a signi®cantly higher provirus load and an increase in CD4 + 25 + T cell population, with a signi®cant, positive correlation. This increase was attributable to polyclonal expansion of HTLV-1-infected cells, as demonstrated by inverse-long PCR analysis of the integration sites. S. stercoralis antigen activated the IL-2 promoter in reporter gene assays, induced production of IL-2 by PBMC in vitro, and supported growth of IL-2 dependent cell lines immortalized by HTLV-1 infection or the transduction of Tax. Taken collectively, these results indicate that S. stercoralis infection induces polyclonal expansion of HTLV-1-infected cells by activating the IL-2/IL-2R system in dually infected carriers, an event which may be a precipitating factor for ATL and in¯ammatory diseases.
SUMMARYStrongyloidiasis, a human intestinal infection caused by Strongyloides stercoralis (S. stercoralis), is difficult to cure with drugs. In particular, a decrease of the efficacy of treatment has been reported in patients dually infected with S. stercoralis and human T-cell leukaemia virus type I (HTLV-I), both of which are endemic in Okinawa, Japan. However, the factors influencing this resistance remain unclear. In the present study, patients infected with S. stercoralis, with or without HTLV-I infection, were treated with albendazole, followed up for one year and separated into two groups, cured and non-cured. The cure rate of S. stercoralis was lower in HTLV-I carriers (P < 0·05). Serum levels of S. stercoralis-specific IgA, IgE, IgG, IgG1 and IgG4 antibodies were estimated, and a decrease of IgE (P < 0·05) and an increase of IgG4 (P < 0·05) were observed in the non-cured group, especially in HTLV-I carriers. RT-PCR of cytokines using peripheral blood mononuclear cells revealed that S. stercoralis patients with HTLV-I showed a high frequency of expression of IFN-g and TGF-b1, whereas those without HTLV-I showed no expression of these cytokines. IFN-g-and TGF-b1-positive HTLV-I carriers showed a decrease of IgE (P < 0·05), an increase of IgG4 (P < 0·01) and a lower cure rate (P < 0·01) compared with those who were negative for both cytokines. These results suggest that persistent infection with HTLV-I affected S. stercoralis-specific immunity and reduced therapeutic efficacy.
Abstract-We analyzed the association of 2 biallelic polymorphisms of CYP11B2 (P450c11AS) gene (1 in the Lys 173 Arg of exon 3 and the other in the promoter at position Ϫ344T/C) with hypertension in 73 hypertensive patients and 134 normotensive subjects. The association between low-renin hypertension and angiotensin I-converting enzyme (ACE) gene was also analyzed. An elevated ratio of plasma aldosterone concentration to plasma renin activity was used to identify low-renin hypertension. Genotypes for CYP11B2 and ACE were determined through polymerase chain reactions. The Arg 173 allele frequency did not differ between hypertensive patients considered as 1 group (34%) and normotensive control subjects (37%). However, only 22% of 58 CYP11B2 alleles studied in 29 patients with low-renin hypertension were Arg 173 alleles, whereas the frequency of this allele was 41% in patients with normal-or high-renin hypertension (Pϭ0.033). An analysis of the distribution of Ϫ344C and Arg 173 genotypes indicated that these 2 variants were in complete linkage disequilibrium: Ϫ344C was present in a subset of chromosomes carrying the Arg 173 (PϽ0.001 in low-renin hypertension). Therefore, the frequency of the Ϫ344C allele was low in the patients with low-renin hypertension compared with those with normal-or high-renin hypertension. Deletion (D) allele frequencies of the ACE gene were 31% in the patients with low-renin hypertension, 39% in the patients with normal-or high-renin hypertension, and 29% in normotensive control subjects. We detected an association between the CYP11B2 gene polymorphisms and low-renin hypertension with inappropriate elevation of aldosterone. The decreased frequencies of the Arg 173 and Ϫ344C variants in the CYP11B2 appear to be genetically linked to low-renin hypertension in the Japanese population studied. Key Words: hypertension, essential Ⅲ cytochrome P-450 Ⅲ polymorphism Ⅲ aldosterone Ⅲ renin-angiotensin system E ssential hypertension is thought to be a polygenic disease. Many gene polymorphisms have been proposed as possible markers for hypertension, including insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene, 1 A1161C polymorphism of the angiotensin II type I receptor gene, 2 and M235T angiotensinogen polymorphism. 3,4 The renin-angiotensin-aldosterone system (RAS) is a key mechanism in the regulation of blood pressure. In addition to the vasoactive action, angiotensin II is a potent stimulus of aldosterone synthesis, which results in sodium and water retention.We have reported that 12.4% of 436 Japanese hypertensive patients had low plasma renin activity (PRA) combined with a normal plasma aldosterone concentration (PAC), resulting in an elevated ratio of PAC to PRA (PAC/PRA), 5,6 and we found that so-called pressure natriuresis was incomplete in this subgroup of patients. 6,7 The inappropriate elevation of aldosterone in such hypertensive individuals suggests persistent mineralocorticoid synthesis despite minimal stimulation of RAS. The biosynthesis of aldosteron...
Abbreviations: AITD, autoimmune thyroid disease; PCR, polymerase chain reaction; TG, thyroglobulin; TPO, thyroid peroxidase.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Association of CTLA-4 Gene A/G Polymorphism in Japanese Type 1 Diabetic Patients With Younger Age of Onset and Autoimmune Thyroid Disease O R I G I N A L A R T I C L EOBJECTIVE -We studied the association between type 1 diabetes with autoimmune thyroid disease (AITD) and A/G allele polymorphism in exon 1 of the CTLA-4 gene in a Japanese population.RESEARCH DESIGN AND METHODS -We studied 74 Japanese type 1 diabetic patients with or without AITD and 107 normal subjects to identify the association between CTLA-4 polymorphism and type 1 diabetes using polymerase chain reaction-restriction fragment length polymorphism analysis.RESULTS -The frequency of the CTLA-4 G allele differed significantly between the type 1 diabetic patients (61%) and the normal control subjects (48%) (P = 0.016). The difference in the CTLA-4 G allele became greater between patients with a younger age of onset of type 1 diabetes (age at onset Ͻ30 years) and the normal control subjects (64% and 48%, respectively). However, the frequency of the CTLA-4 G allele did not differ between type 1 diabetic patients with younger and older age of onset (64% vs. 57%). The G allele frequencies in the patients with younger-onset type 1 diabetes and AITD increased more than in the control patients (P = 0.025). These differences reflected a significant increase in the frequency of G/G genotype-that is, 54% in those with younger-onset type 1 diabetes and AITD, 39% in those without AITD, and 28% in control subjects.CONCLUSIONS -An association was detected between the CTLA-4 gene polymorphism and younger-onset type 1 diabetes with AITD. The G variant was suggested to be genetically linked to AITD-associated type 1 diabetes of younger onset in this Japanese population. The defect in these patients presumably lies in a T-cell-mediated autoimmune mechanism. E p i d e m i o l o g y / H e a l t h S e r v i c e s / P s y c h o s o c i a l R e s e a r c h 976DIABETES CARE, VOLUME 23, NUMBER 7, JULY 2000 CTLA-4 gene A/G polymorphism in type 1 diabetes and AITDtide level of Ͻ20 µg/day (20). Blood was sampled at intervals of 6-12 months for the measurement of the thyroid autoantibodies (anti-thyroid peroxidase [TPO] and anti-thyroglobulin [TG] antibodies), GAD65 antibody, and IA-2 antibody. Antibodies were determined by radioimmunoassay (20,21). Cutoff levels of GAD65 antibody, IA-2 antibody, and thyroid autoantibody were 1.2, 0.5, and 0.4 U/ml, respectively. Thyroid autoantibodies were measured Ͼ3 times in all patients with diabetes during the follow-up period. When the thyroid autoantibodies were detected Ͼ2 times in same patient, autoantibodies were considered to be positive. The diagnosis of AITD was based on the finding of palpable goiter or the presence of chronic thyroiditis with ultrasonography examination in the...
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